Preparation of esters of 7-halogeno-cholesterol



where R is a saturated open-chain hydrocarbon Patented Nov. 28, 1950 PATENT OFFICE PREPARATION OF ESTERS OF 7-HALOGENO- CHOLESTEROL Ewart Ray Herbert Jones, Austin Ernest Bide,

and Ralph John Nicholls, London, England, assignors to Glaxo Laboratories Limited, Greenford, Middlesex, England, a British company No Drawing. Application February 17, 1947, Se-

rial No. 729,192., In Great Britain February 25,

6 Claims.

This invention is concerned with improvements in and relating to the preparation of derivatives of cholesterol, which substance may be represented by the formula 15 residue.

It is known that the 7-dehydro-derivative of cholesterol which has an additional double bond in the '78 position, is a provitamin and on irradiation with ultraviolet light leads to vitamin D3.

British Patent 574,432 describes a process for the preparation of 'Y-dehydro-derivatives of certain sterols including cholesterol, in which a 3- ester of the sterol is reacted with a suitable N- es halogenated acid amide or imide, preferably N- brommosuccinimide and the resulting halogenated product is 'dehydrohalogenated with a suitnoted that the isolation of the pure 7-halogenocholesteryl esters from the reaction product forms no part of the present invention although it can in some cases be accomplished by normal my,

methods.

In general the products obtained by the present process will be used for conversion to the corresponding 7-dehydrocholesteryl esters from which 7-dehydrocholesterol may be obtained by hyare drolysis. It should further be noted that the 7- halogenocholesteryl esters themselves cannot conveniently be hydrolysed as such without losing their halogen.

The method according to the present invenwhere X is chlorine or bromine, the former being preferred and R1, R2 and R3 arelower' alkyl groups such as methyl, ethyl or propyl. W prefer to use compounds in which the group is tertiary butyl or tertiary amyl. Compounds of the above general formula will hereinafter be referred to as halogenators.

According to the invention therefore we provide a process for the preparation of steroid substances which are rich in 7-halogenocholestery1 esters in which a suitable 3-ester of cholesterol as herein defined is reacted with a halogenator as herein defined.

We prefer to carry out the reaction with a solution of the cholesteryl ester in a solvent as herein defined and it is also preferable that the reaction should take placein the presence of an organic peroxide such for example as benzoyl peroxide or acetyl peroxide.

The term suitable ester as used herein means an ester of a carboxylic acid, excluding any ester, the acyloxy fragment of which contains any grouping which reacts either with the halogenator or with the halogenated cholesterol, it being understood that the term acyloxy is used in its broad sense and does not merely imply derivatives of aliphatic acids. It may be stated that we prefer to use cholesteryl acetate.

As solvent for the cholesteryl ester we prefer to use carbon tetrachloride, but we may use any solvent for the ester which is inert or substantially inert to the halogenator to be used. It may here be noted that some solvents such as aliphatic hydrocarbons or mixtures thereof and ethers react readily with halogenators of the above stated general formula, and are therefore not suitable for use.

We prefer to use equimolecular proportions of the cholesteryl ester and halogenator and to carry out the halogenating reaction at the boiling point of the solvent, but lower temperatures may be employed, in which cases it will be desirable to keep the reaction mixture agitated.

The reaction is preferably continued until the steam bath for 20 mins. =-any separated inorganic salts are removed by hot mixture contains no active halogen, by which We mean no halogen which will cause the appearance of iodine When the mixture is shaken with an aqueous solution of potassium-iodide.

When thelhalogenation reaction has been completed we may remove the solvent, preferably under reduced pressure when there will be left a mixture of halogenated steriods containing a substantial proportion of V-halogenochole'stersfl ester.

This product will be found to .be suitable for dehydrohalogenation in the manner described'in the said prior specification, so "as to obtain the 7-dehydrocholestery1 ester, which can ,of course be hydrolysed to form 7-dehydrocholestero1.

Where it is intended to dehydrohalogenate the above mentioned mixture, we may add the tertiary organic base used for this purpose to the solution obtained as a result of the halogenation reaction before removing the solvent and then complete theprocess as described in the said prior tion theexamples also-describe theconversion of rthe products obtained into T-dehydrocholesterol and .the yields thereof obtained.

Examples (1) Twenty-eight g. of cholesteryl acetate are dissolved in 125 ml. of carbon tetrachloride, followed by 0.1 g. of benzoyl peroxide. 7.1 g. of freshly prepared tert-butyl hypochlorite are now :added, and the reaction mixture heated on the steam bath under reflux, until the addition of one drop of the reaction mixture to an-aqueous solution of potassium iodide results in no immediate liberation of iodine. This usually takes 15-25 minutes.

7 The solvent is now removed from "the reaction .mixture by heating in vacuo, and the residueof halogenated steroids is dissolved in ten times its .weight of diethylaniline.

Dehydrohalogenation is effected by heating the-diethylaniline solution rapidly to the boiling point -maintaining there for 10 -mins., and then pouring the hot solution onto 500 g. of crushed ice.

The united extracts are washed with 2 separate quantities of 500 ml. of 10% w., v. hydrochloric acid, and then once with 250 ,ml. of 5% aqueous sodium carbonate solution.

The petroleum ether is then removed by distillation in vacuo, and to the residue of sterol acetates are added 90 .mls. of a 5% ethyl alcoholic solution of caustic'potash. Saponification is carried out by refluxing the mixture on the At the end of this time filtration, and the filtrate is allowed to stand in the refrigerator over-night.

The precipitated crystals are collected, washed with 7.5 ml. .of 90% ethyl alcohol, and then with undiluted ethyl alcohol until substantially free from colour.

There are-obtained-in thiswa -20 g. of material containing 15-20% of :the desired 'Z-dehydrocholesterol.

(2) Twenty-eight g. of cholesteryl acetate are dissolved in 125 ml. of carbon tetrachloride and 10 g. of tert-butyl hypobromite areadded. The

The mixture is extracted with 75011111. of petroleum ether (B. P. 60-80), and thenthe aqueous solution re-extracted with 500 ml. of the same solvent.

4 mixture is heated at the boiling point until there is no longer present any active halogen, which generally takes about 5 minutes.

The solvent is removed in vacuo with the applicationof gentle heat, and 46 ml. 10f diethylaniline are added to the residue. The resulting solution is heated for 3 hrs. on the steam bath with gentle stirring. At the end of this time, themixture is cooled and 150 m1. of petroleum ether (B. P. 60/80 C.) are added. The precipitated diethylaniline hydrobromide is filtered off, and the excess diethylaniline in the petrol solution removed by washing with acid.

The resultingsolution of sterol acetates is then saponified with alcoholic potash and further treated as described in Example (1) to yield a product containing about 16% of the desired 7 -dehydrocholesterol.

(3) Twentweight g. of cholesteryl acetate and 0.1 g. of benzoyl peroxide dissolved in ml. of

carbon tetrachloride are treated at the boiling point with a solution :of 8 g.-of tert-a-mylhypo- "chlorite in .50 ml. of carbon tetrachloride added where R R and'R; are alkyl groups having not more than threecarbon atoms and X is selected from the group consisting of .chlorine and bromine.

2. The process defined in claim '1 in which "the reaction is carried out in the "presence of an organic Peroxide.

3. A process .for the preparation of 7-halogeno derivatives of cholesteryl acetate in which a'mixture of cholesteryl acetate in carbon tetrachloride is reacted with a compound of the general formula where R R and R3 are alkylgroups having .not more than three carbon .atoms and X is selected from the ,group consisting of chlorine and bromine.

4. The process defined in claim .1 .in which the halogenating compound .is tertiary amyl hypochlorite.

5,. .Aprocess for the preparation of 7halogenocholes'terylesters of carboxylic acids which comprises reacting in carbon tetrachloride approximately equimolecular proportions of a carboxylic acid ester of cholesterol and a halogenating compound of .the general formula R1 RQCLOX where R R. and R are alkyl groups having not more than three carbon atoms and X is selected from the group consisting of chlorine and bromine, the reaction being carried out at the boiling point of the reaction mixture 6. A process for the preparation of carboxylic acid esters of 7-chlorocho1esterol comprising reacting a carboxylic acid ester of cholesterol dissolved in carbon tetrachloride with tertiary butyl hypochlorite.

EWART RAY HERBERT JONES. AUSTIN ERNEST BIDE. RALPH JOHN NICHOLLS.

REFERENCES CITED The following references are of record in the file of this patent:

6 UNITED STATES PATENTS Number Name Date 2,403,683 Reichstein July 9, 1946 2,441,091 Vliet May 4, 1948 FOREIGN PATENTS Number Country Date 574,432 Great Britain Jan. 4, 1946 OTHER REFERENCES Cohn, Arbeits Methoden fur Organisch- Chemische Laboratorien, Speziellen Teil, 5th Ed, 1923, page 252.

McBee, Chem. Trade Jour. and Chem. Eng.,

15 April 4, 1941, page 199.

Ziegler, Annalen 551, pages 93-104 (1942). 

1. A PROCESS FOR THE PREPARATIONOF 7-HALOGENOCHOLSTERYL ESTES OF CARBOXYLIC ACIDS WHICH COMPRISES REACTING A MIXTURE OF CARBOXYLIC ACID ESTER OF CHOLESTEROL IN ARBON TETRACHOLIRDE WITH A HALOGENATING COMPOUND OF THE GENERAL FORMULA 